It is estimated that 10 percent of pancreatic cancers have a strong heritable component and families with at least one pair of first-degree relatives with pancreatic cancer are termed familial pancreatic cancer kindreds. Recent advances in sequencing technology have provided a new ability to search, in an unbiased way, for the genes underlying disease susceptibility. In this way, PALB2 and ATM were recently identified as familial pancreatic cancer genes. However, the genetic basis of 85-90 percent of patients with familial pancreatic cancer is unknown and other familial pancreatic cancer genes are yet to be discovered. To understand fully the genetic basis of familial pancreatic cancer, I will analyze the genomes of over 750 familial pancreatic cancer patients to identify candidate predisposition genes. I will then comprehensively characterize candidate familial pancreatic cancer genes using in vitro and in vivo models of pancreatic cancer. In Aim 1, I will apply bioinformatic approaches, to analyze the normal and tumor genomes of the 750 patients and identify candidate familial pancreatic cancer genes. These analyses will take place during the K99 phase. In Aim 2, I will extensively characterize candidate familial pancreatic cancer genes using pancreatic organoids, a three-dimensional culture system derived from primary pancreatic duct cells. This system will be validated with known susceptibility genes during the K99 phase, with assessment of candidate genes during the R00 phase. Finally, in Aim 3, I will utilize the unique sequence dataset available to me to understand the role environment plays in modulating pancreatic cancer risk. Specifically, I will explore the role of local pancreatic inflammation (pancreatitis) when superimposed on a genetic predisposition to pancreatic cancer, e.g. carriers of a deleterious BRCA2 variant, and the potential of chemoprevention strategies to ameliorate pancreatic cancer risk. The Johns Hopkins University provides a unique and supportive atmosphere in which to develop an independent research program. In addition, during the K99 phase I will receive mentorship and guidance from a truly distinguished team of mentors: Drs. Vogelstein, Hruban, Papadopoulos, and Tuveson. Under their guidance I will obtain new skills and experience with in vitro and in vivo models of pancreatic cancer, while reinforcing my expertise in genetic and the analysis of high-throughput sequencing data. With the opportunities afforded by the K99/R00 Career Development Award, I will be fully able to develop an independent research program and pursue my long-term scientific objectives of furthering our understanding of familial pancreatic cancer, and translating these developments into personalized patient care.